Psychiatrist Shares His Experience With GLP1 Weight Loss Drugs with Dr Rodrigo Mansuer

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies, such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will. Help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Welcome back to Metabolic Mind, a nonprofit and initiative of Baszucki Group. We’re embarking on this series to talk about this concept of use of GLP-1 receptor agonist, medications like Wegovy and Ozempic, in a specific psychiatric population, whether it’s for medication-induced weight loss, or whether it’s for treating psychiatric symptoms. And this is really controversial because they are medications that have some side effects and some potentially serious ones that we’ve discussed.

Whether it’s increased suicidal ideation, whether it’s stomach paralysis, side effects are rare, as they tend to be, but when they’re really serious, they raise concern. But we’re hearing reports online and from clinicians and researchers that these medications may actually help with psychiatric symptoms. So, how do we balance whether or not to use these medications?

I was so fortunate to meet Dr. Rodrigo Mansur, who is actually studying this exact question. Now, Dr. Mansur is a Staff Psychiatrist at the University Health Network in Toronto, and an Associate Professor in the Department of Psychiatry at the University of Toronto. And he is both a clinician and a researcher.

So, he has to decide, how do I treat this patient in front of me? And he’s on the forefront of studying these medications. So, as we weigh the risks and benefits, should we use Ozempic, Wegovy, GLP-1 receptor agonist in a specific psychiatric population, either for medication-induced weight gain or to treat symptoms, how do we determine that?

I think he’s one of the best people I could have possibly asked. So, I hope you enjoy this brief interview, and that it’s helpful for you to help you understand sort of the risks and benefits and how to discuss this with your physician. And quickly, before we get to the interview, remember our channels for informational purposes only. We’re not providing individual or group medical or healthcare advice, and we’re not establishing a doctor-patient relationship.

Any changes to your lifestyle or medication can be dangerous if not done without supervision. So, always check with your healthcare team and your physician before changing medications, before changing your lifestyle, and not acting on any of the discussion we have today on your own.

All right, so with that, let’s get on with this interview with Dr. Rodrigo Mansur.

Dr. Mansur, I want to thank you for joining me today to really help us dig deeper into this important and sort of controversial topic of the use of the GLP-1 receptor agonists, specifically in a psychiatry population. We’ve talked in prior videos already about the problem of medication-induced weight gain, and clinicians and patients wanting to do everything they can to try and combat that.

One of them being the use of Wegovy, Ozempic, and the like of the GLP-1 receptor agonist. But there’s some controversy about the use in this specific population. Some reports of improved mood, improved symptoms, some reports of potentially increased suicidal thoughts.

And so, how do we make sense of all this? And so while I’m researching this, I come across you, who was perfect to come on and talk about this because you’re doing research using these medications, specifically to see how they target psychiatric symptoms. So, please give us a little bit of your background, and what brought you or made you interested in doing this line of research.

Rodrigo: 
Sure, I’m a psychiatrist. I’m a clinician scientist, and an associate professor of psychiatry here at the University of Toronto. In our research program, we work with people affected by mood disorders, depression and bipolar disorder. We have worked trying to understand better what causes the metabolic comorbidities, right?

What causes weight gain, development of diabetes, for example, in someone with depression and bipolar disorder. And I also have much an interest in translating these findings into clinical applications, into novel treatments. And we’ve been working on this idea of using GLP-1 receptor agonist for almost one decade now with a dual purpose, right?

Targeting the metabolic comorbidities. So, improving the metabolic health in individual affected by these conditions. But we’re also very much interested in finding out if these medications can also be used to target the core symptoms of mood disorders, the emotional aspects of disorders, the anhedonic symptoms of issues of motivation, enjoyment, interest, as well as, which is directly related to the work we do, the cognitive symptoms of depression, difficulties of attention, concentration, focus, which are very common in this population.

And our interest in GLP-1 receptor agonists comes from a variety of sources. These are well-known, effective medications for weight management. But they also have important effects on the central nervous systems, right? So, these are not just purely peripheral medications, the systems that they target. The GLP-1 system, the GLP-1 receptor is, for example, expressed in the brain, is expressed in different areas of the brain, including areas that have been traditionally implicated in mood and other psychiatric disorders.

So, it makes us wonder as if there is potentially a deeper connection there. 

Bret: 
Yeah, I think that’s such an interesting point that a lot of people don’t realize that with all the focus on weight loss, the focus is on how these medications work in the gut, in the GI system, on the hunger, how their incretins, right?

And then, and how they work on how hungry you are, how much food you’ll eat and so forth. But we don’t think so much about a lot of that is a brain effect, like a hunger effect is in our brain. So, what other brain effects might they have? So, has there been a signal that you’ve seen that by targeting these receptors in the brain, that it does directly impact someone’s mood, someone’s thought process, someone’s mental health?

Rodrigo: 
Yeah, the preliminary data is that it has. Preliminary being a very key word here as this is a relatively novel area of research. So, there are by now a few studies using GLP-1 receptor agonist or incretin-based treatments in primarily psychiatric populations. We done a little pilot study with Liraglutide a few years ago.

It was a mouse study. It was an open label study. So, there wasn’t a placebo. It wasn’t well controlled, as well controlled as a classical randomized clinical trial is. But in our study, we did observe improvements in mood. We did observe improvements in cognitive function, which were related to improvements in the metabolic systems. They were, for example, associated with weight gain but not completely.

Some of these effects seem to be independent from, for example, weight loss, which has been shown by other groups as well. There are a few studies also using these medications to improve, for example, cognitive function in individuals with diabetes. A recent study also documented an improvement in attention, learning and memory independent from weight loss.

Again, all very early. This is a rapidly evolving field. But there are definitely signs pointing this direction, that these drugs, yes, can have direct effects on the central nervous system. And therefore, can also directly affect mood, behavior, thinking, concentration, and et cetera.

Bret: 
Yeah, a couple really important points there. One that it’s early science, but that’s how you do science. That’s how you progress. You’ve got to start somewhere. And frequently, clinical practice and hypothesis are ahead of where the science is, and that’s okay. It takes people like you to help us catch up.

And two, how much is related to the metabolic health improvements and how much is related to a direct CNS drug effect? And with early data, it’s hard to know for sure. But it sounds like there’s a signal that it’s a little bit of both. And I think that’s important, too, because we talk a lot about the connection of metabolic and mental health and how improving metabolic health will have direct effects on improving mental health.

But perhaps, this can go beyond it? But you’re talking about symptoms of attention and focus. What about the symptoms of depression and anxiety or maybe even mania or psychosis? Like as we get into more serious mental illness, is there a signal there as well that there could be an effect?

Rodrigo: 
Some, again very, very preliminary data. There was one study using liraglutide, one of the GPL-1 receptor agonists for weight management in people with psychosis or psychotic spectrum disorders. And they did not, that study, observe any kind of deleterious effect on their symptoms.

it wasn’t a study designed to improve or to treat psychotic disorders with these conditions. But, of course, as safety measures, they did assess the evolution of psychotic symptoms throughout the trial and found that there was no major effect. So, patients were not necessarily getting worse.

In our pilot study, we did measure mood symptoms. We did measure anhedonic symptoms as well. So, enjoyment, motivation, and patients actually improved there. Again, small open label, far from being definitive. But there was a consistent signal, at least, or a promising signal telling us that there might be something there worth exploring more.

Bret: 
Yeah. Now, so it sounds like there’s enough, certainly enough, of a signal to say we should look into this further, which is exactly what you and your team are doing, which I think is fantastic. But what about the signals in the opposite direction? We saw a report that European regulators were investigating potentially increased suicidal ideation. And the fact that when the FDA looked at the studies to approve these medications, none of those studies included anybody with a psychiatric diagnosis or taking medication.

So, how do you balance that with doing the research and looking forward the pros and the cons, basically? 

Rodrigo: 
Yeah, we have to be mindful of this possibility, right?

Especially, if you consider that these systems are connected, right? As you alluded, we know by now that there is a connection between mood and metabolism, and which is one of the ideas underlying the use of these medications in psychiatric populations, right? Yes, they affect the central nervous system.

They affect the food intake system, but this system does not exist in a vacuum, right? This is a system that is connected with other system in the brain it informs, it constraints the function in very important ways of other systems in the brains. And it can affect behavior, right? And you can certainly see it affecting behavior in a variety of different ways, right?

Not necessarily in the positive therapeutic way. It wouldn’t be the first time that promising weight loss medication has negative effects on mental health. I’m not sure if you heard about a medication called rimonabant, which is a modulator of the endocannabinoid system, which was approved a few years ago for weight loss. But it had to be removed from the market because of worsening of depressive symptoms in emerging suicide ideation.

Now, completely different medication, completely different mechanism of action than the GLP-1 receptor agonist, but there is a precedent there to be mindful about the possibility of these medications having a significant effect on mood and not necessarily in the direction we want. So, I think being aware of it, and being careful when using these medications in psychiatric populations, and in our case when designing studies is definitely necessary.

So, we are currently doing a clinical trial with oral semaglutide. Semaglutide is the same medication as Ozempic. There is a oral form called Rybelsus, which is what we are using in a population with depression. Our goal in this study is to treat depression and to treat its cognitive symptoms. And we are more or less now halfway through this trial.

So our goal is to treat 60 people with it. We have done a little over 30 by now, and this is a placebo controlled trial, right? At this point, we don’t know yet, who is taking what. But we do know that the majority of people are either improving in terms of depressive symptoms, or they’re at least not getting worse.

We haven’t yet gotten any kind of signal of worsening, and we also haven’t yet seen any emergent suicidal ideation, which are things we measure consistently, frequently, every visit using standardized measures. And we have as part of a trial, which is standard in these situations, built-in criteria as well.

If someone starts deteriorating from their perspective, it triggers a warning, right? And it, we have to assess further. That hasn’t happened yet. It’s still early. It’s still halfway through the trial. And still, as I mentioned, we have not broken the blind. So, we don’t know yet who’s taking what.

So, I cannot say that people are getting better because of it. It might be the placebo effect, which we know does wonderful things. But at the very least, I can tell, okay we’re not seeing that or haven’t yet seen these warning signs. 

Bret: 
Yeah. And how many people are enrolled, and how long is the trial meant to be?

Rodrigo: 
People use semaglutide or placebo for 16 weeks. We have enrolled 35 people by now, and we have 21 that completed the full 16 weeks. 

Bret: 
Great. Yeah, and I like how it’s so important that you have those built-in safety measures. So, you are on the forefront of research on this topic.

You’re leading the way, but you also have a clinical practice. And that balance of here’s a patient right in front of me at this moment that I’m trying to help, and I don’t have the results of the trial. Even your own trial, you don’t have the results of. So, how do you make sense of all this to say, how do I help this person in front of me?

Do I prescribe this medication? Do I not? How do I weigh it? 

Rodrigo: 
Yeah, it is a clinical decision, right? It is still, at this point and for the foreseeable future, would be off-label indication to use it for weight loss in a primary psychiatric population. But we do have some evidence that we can rely on.

We do know that these medications are safe to be used for people that are not diabetic. So, both semaglutide and liraglutide, they have indications for weight management. And most other medications, including the newer generations, like tirzepatide, which is the dual GLP-1 receptor agonist, we have already trial showing that it’s quite effective for non-diabetic populations.

It’s also safe. It does not promote, one of the concerns about these are anti-diabetic medications, right? So, we always have the concern of causing hypoglycemia or the lowering of blood sugar, and these drugs are very, very safe from the perspective. The risk of hypoglycemia is very, very low. So, they can be safely used for people that do not have diabetes.

We have to be, again, mindful and aware of the potential with known risks, given that we don’t have still a robust body of evidence using these medications in populations with primary psychiatric disorders. But we do have, again, some studies here and there. Most of the signal is in the positive direction, is in the safe direction.

So yes, we should carefully monitor mood. We should carefully monitor suicide ideation, which is true every time we prescribe something for someone with depression or someone with bipolar disorder. But it’s certainly true here. The efficacy, however, in terms of weight management, we have no reason to believe that it is any different than someone that has depression and bipolar disorder compared to the populations where these medications were tested, meaning obese people that do not have a diagnosed psychiatric comorbidity.

Now, that’s still tricky to ascertain because the causes of obesity, in a way, are fairly different than someone that has depression and bipolar, right? Again, given the known connections between mood and metabolism.

But most of it indicates that they are also quite effective at promoting safe weight loss. 

Bret: 
Now, we focused on the medications up to this point, but I think we also have to acknowledge that medications aren’t a cure all. So, we also have to talk about lifestyle. What, how do you see the need for lifestyle interventions as well?

Rodrigo: 
So, I can tell you then that the success of the GPL-1 receptor agonist has not yet changed the whole calculus on managing metabolic comorbidities in patients with mood and psychotic disorders. So, the recommendations are still first to address and, when possible, intervene on lifestyle.

So, to provide good quality information on diet to facilitate as much as an individual usually can, regular physical activity, and to address psychiatric medications that have a potential causative effect on weight gain. So, when possible, avoid the agents more clearly associated with weight gain.

And we do now have nowadays a few newer alternatives that less risk in others. So, when possible to remove, let’s say the offend the agents and go to a safer, easier to use alternative. And when these are not enough, that’s when you go to the pharmacological approaches for weight management.

And what the GLP-1 receptor agonists have done is to broaden the possibilities there. They should not necessarily be the first line. There is very good quality evidence on the efficacy and safety of metformin, which is a widely available, very affordable agent, which is an important question also when it comes to GLP-1 receptor agonist here.

Metformin does work well at managing weight gain from psychiatric medications. And it is something that I use quite often in my clinical practice. You also have Contrave, which is a bit more complicated to use in psychiatric population. Is does contain psychotropic medication bupropion, which has to be considered.

But when these are not effective or where there is a contraindication to one of these, then I think going to a GLP-1 receptor agonist is, again, being mindful of how early it is in terms of the use of these medications in psychiatry, the potential risks. I do think that there is a use for them in clinical practice.

Bret: 
I thought that was a really interesting discussion. And I’m glad I got to talk to Dr. Mansur, who really is on the cutting edge of this research. And as a clinician, and he’s obviously very thoughtful, very balanced about how to approach this like a scientist should be. We have to recognize this isn’t going to be, at this point, an easy absolutely, yes.

Use it, absolutely. No, don’t use it. There’s a middle ground, and there’s experimentation. And the key is to be cautious, and to be balanced. And to make sure the discussion between the patient and the doctor is very thorough exploring these things. So, we’ve already had a couple videos exploring this.

Hopefully, we’ll have some more. So, stay tuned for those as we delve deeper into this evolving and very hot topic. So, thank you so much for joining us at Metabolic Mind, a nonprofit initiative of Baszucki Group. I’m Dr. Bret Scher, and we look forward to seeing you in our next videos. And again, please leave a comment.

Let us know your experience, either with using GLP-1 receptor agonists or medication-induced weight gain. What’s worked, what hasn’t worked, what you’ve tried. We’d love to learn from you as well. So, thank you very much, and we’ll see you here next time at Metabolic Mind. Thanks for listening to the Metabolic Mind Podcast.

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